(a) Field of the Invention
The present invention relates to 3-oxiranyl benzoic acids and derivatives thereof and their pharmaceutically acceptable salts. Compounds of the present invention are useful in treating inflammatory conditions in mammals such as psoriasis, Crohn's disease, ulcerative colitis, arthritis, gout and the like. Compounds of the present invention are inhibitors of epoxide hydrolases, specifically leukotriene A.sub.4 (LTA.sub.4) hydrolase which catalyzes the biochemical transformation of LTA.sub.4 into leukotriene B.sub.4 (LTB.sub.4) which is a potent proinflammatory agent.
(b) Prior Art
LTB.sub.4 has been implicated as an important mediator of inflammation due to its potent proinflammatory properties. In neutrophils, LTB.sub.4 production from the unstable allylic epoxide LTA.sub.4 (Formula I) is catalyzed by a cytosolic enzyme LTA.sub.4 hydrolase. ##STR2##
LTB.sub.4 (Formula II) is an arachidonic acid metabolite which is produced by the 5-lipoxygenase pathway. Pharmacologically, LTB.sub.4 is an important mediator of inflammation in mammals. As a mediator of inflammation, LTB.sub.4 is known to induce chemotaxis, chemokinesis, aggregation, and degranulation of leukocytes in vitro, and to induce accumulation of polymorphonuclear leukocytes, and increase vascular permeability and edema formation in vivo. ##STR3##
Particularly high levels of LTB.sub.4 are detected in lesions in inflammatory diseases such as rheumatoid or spondylarthritis, gout, psoriasis, ulcerative colitis, Crohn's disease, and some respiratory diseases.
Accordingly, it is an object of this invention to produce compounds for use as pharmaceutical agents which will inhibit LTB.sub.4 activity in mammals by inhibiting LTA.sub.4 hydrolase and preventing the formation of LTB.sub.4.
U. K. Patent Applications GB 2177401 A and GB 2144422 A and their European counterpart EP-134111-A generically disclose compounds of the formula ##STR4## in which R.sup.1 is an alkenyl or alkynyl group optionally substituted with an optionally substituted phenyl group and containing from 5 to 30 carbon atoms and, R.sup.3, R.sup.4, and R.sup.5 are each selected from hydrogen, carboxyl C.sub.2-5 alkoxycarbonyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxyl, optionally protected tetrazolyl, halo, trifluoromethyl, nitrile, nitro, and --CONR.sup.10.sub.2 where each R.sup.10 is hydrogen or C.sub.1-4 alkyl. These compounds are intermediates useful for preparing pharmaceutical compounds of the formula ##STR5## in which n is 0, 1 or 2, R.sup.1 is hydrocarbyl group optionally substituted with optionally substituted phenyl group containing from 5 to 30 carbon atoms, R.sup.2 is optionally substituted phenyl or C.sub.1-10 alkyl optionally substituted by one or more substituents selected from optionally protected hydroxyl, optionally protected carboxyl, nitrile, optionally protected tetrazolyl, --COR.sup.6 where R.sup.6 is C.sub.1-4 alkyl, C.sub.1-4 alkoxy, an optionally protected amino acid residue or --NR.sub.2.sup.7 where each R.sup.7 is hydrogen or C.sub.1-4 alkyl, and --NHR.sup.8 where R.sup.8 is hydrogen, a protecting group, an optionally protected amino acid residue, C.sub.1-4 alkyl or --COR.sup.9 where R.sup.9 is C.sub.1-4 alkyl or C.sub.1-4 alkoxy, and R.sup.3, R.sup.4 and R.sup.5 are each selected from hydrogen, carboxyl, C.sub.2 5 alkoxycarbonyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxyl, optionally protected tetrazoyl, halo, trifluoromethyl, nitrile, nitro and --CONR.sup.10.sub.2 where each R.sup.10 is hydrogen or C.sub.1-4 alkyl; and salts thereof. These compounds in unprotected form, are disclosed to be pharmacologically active in tests which demonstrate their antagonist effect on leukotriene receptors and indicate their use in the treatment of allergic disorders.
J. Evans, et al., PROSTAGLANDINS, LEUKOTRIENES AND MEDICINE, 23: 167-171 (1986) discloses compounds which inhibit rat and human neutrophil LTA.sub.4 hydrolases; however, these compounds are structurally different from compounds of the present invention.
The pharmacology of the biologically active leukotrienes is generally discussed in J. CLIN. INVEST. 73: 889-897 (1984).